Macitentan in Pulmonary Hypertension of Sickle Cell Disease

Background and Rationale:

Sickle cell disease (SCD) affects 250,000 births per year worldwide, with 70-80,000 patients
currently residing in the US. Although classically thought of as a genetic hemoglobinopathy,
most of the clinical complications are vascular in etiology and pulmonary manifestations are
the primary cause of morbidity and mortality. Pulmonary hypertension (PH), one such pulmonary
complication, occurs in 6-10.5% of SCD adults and is associated with a 60% four-year survival
[1-4]. No specific therapy for PH in SCD exists representing an area of intense clinical need
in this field.

Clinical trials of pulmonary vasodilator medications in PH of SCD have been problematic.
There have been no randomized placebo controlled trials of any traditional pulmonary arterial
hypertension (PAH) medication completed in this population to date [5, 6]. Three randomized
placebo-controlled trials have been undertaken previously. Two compared treatment with
bosentan to placebo in SCD patients with right heart catheterization (RHC)-defined elevated
pulmonary vascular resistance (PVR) with a normal pulmonary capillary wedge pressure (PCWP)
(the ASSET-1 trial) or pulmonary venous hypertension (PVH) with a PVR > 100 dynes.sec/cm5
(the ASSET-2 trial) [5]. After the randomization of only 14 subjects in ASSET-1 and 12
patients in ASSET-2, the trials were prematurely terminated due to slow patient enrollment.
Although very few patients were enrolled, there were no apparent toxicity issues. The third
trial, Walk-PHaSST (Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy)
[6], compared the safety and efficacy of sildenafil to placebo in SCD patients with a TRV
≥2.7m/s. After 74 (of a targeted 132) subjects were enrolled, the study was prematurely
discontinued due to an increase in serious adverse events in the sildenafil group, primarily
hospitalization for pain.

There are a number of possible explanations for these failed trials:

1. The hemodynamics of PH in SCD reflect a spectrum of abnormalities. Approximately 40-50%
of PH in SCD patients have hemodynamics similar to other forms of PAH; a mean pulmonary
arterial pressure > 25 mmHg, normal left-sided filling pressures (PCWP or left
ventricular end diastolic pressure < 15 mmHg) and an elevated PVR [1, 3]. But at least
50% of PH in SCD patients have at least some degree of PVH usually due to diastolic
dysfunction of the left ventricle [7]. How an elevated PVR is defined in PH of SCD is
controversial. While typically in other forms of PAH, it is defined as 3 Wood units or
240 dynes.sec/cm5, this is reflective of a normal PVR of 120-160 dynes.sec/cm5. In SCD,
the anemia-induced elevations in cardiac output observed in these patients produce a
baseline PVR of 60-100 dynes.sec/cm5 suggesting that a PVR of 160 dynes.sec/cm5 or 2
Wood units may be a more appropriate value [8].

2. SCD is considered to be a rare disease in the US according to the NIH. As PAH of SCD
probably only occurs in 2-4% of HbSS adults, many centers in the US will only have a few
(<10) eligible patients for enrollment even under the best circumstances. SCD patients
often have co-morbidities limiting their participation in clinical trials, which often
decreases this number even further.

3. The epidemiology of PH in SCD has been evolving over the past 10-15 years. Numerous
studies demonstrated an elevated pulmonary artery systolic pressure (PASP) by
echocardiography reflected by an elevated tricuspid regurgitant jet velocity (TRV) was
present in 1/3 of HbSS and 10-28% of HbSC adults[9-11]. However, an elevated TRV only
has approximately a 25% positive predictive value for PH in SCD [1]. The need for a
right heart catheterization to confirm a diagnosis of PH in SCD has only been gaining
clinical acceptance over the past few years and when the prior clinical trials were
conducted, this was not a standard part of the PH workup in these patients.

Given the serious limitations of the randomized trials, our clinical guidelines committee
decided that its judgments regarding whether targeted PAH therapy is indicated in SCD
patients with an elevated PVR and normal PCWP should be informed by indirect evidence from
Group 1 PAH populations and our own clinical experience. In Group 1 PAH patients, it has been
well-established by meta-analyses of randomized trials that targeted PAH therapy consistently
improves exercise capacity, functional status, symptoms, cardiopulmonary hemodynamics and
outcome [12-14]. This indirect evidence is supported by four case series in which SCD
patients with RHC-confirmed pre-capillary PH received targeted PAH therapy with bosentan,
sildenafil, and/or epoprostenol. Targeted PAH therapy was associated with improvement in
exercise capacity, with the six minute walk distance increasing 41 to 144 m beyond baseline
[15-18]. There were also improvements in the mean PAP, PVR, and cardiac index, although these
parameters were measured in only a few patients [18]. The magnitude of the benefits was
greatest among symptomatic patients. The most common adverse effects were headache (15%) and
peripheral edema (21%); transaminase elevation was reported in 14% of patients during
endothelin receptor antagonist therapy [15-18]. Based upon these results and the increased
morbidity associated with sildenafil use, we are weakly recommending a trial of either a
prostanoid or an endothelin receptor antagonist for select patients with SCD who have a
RHC-confirmed marked elevation of their PVR, normal PCWP, and related symptoms [8].

The FDA approval of macitentan for treatment of PAH represents a unique opportunity for study
of the use of this medication in SCD. Endothelin-1 has long been established as an important
mediator of vasoconstriction in SCD [19, 20] and more recent studies have implicated a role
for this molecule in mouse models of PH in SCD [21]. PH and an elevated TRV are both
independent risk factors for mortality in SCD [1, 2, 9, 22] and, as the median age of death
of SCD patients is in the 5th decade irrespective of a PH diagnosis, the possibility of
therapeutically altering this outcome is of key importance in this disease. With the
publication of the American Thoracic Society sponsored clinical guidelines for the diagnosis
and treatment of PH in SCD (additionally endorsed by the Pulmonary Hypertension Association
and the American College of Chest Physicians), the timing for re-addressing the possibility
of a clinical trial of a PAH therapy in this population perfect. We propose to utilize the
information gathered from the trials which proceeded it to specifically design a clinical
trial using macitentan to treat the SCD patients most likely to respond to this therapy;
those with PAH-like hemodynamics without co-existent left-sided heart disease.

Hypotheses:

1. Macitentan will be safe for treatment in patients with PAH of sickle cell disease

2. Macitentan will improve hemodynamics, exercise capacity and quality of life in patients
with pre-capillary pulmonary hypertension of sickle cell disease

3. Long-term use of macitentan will improve survival in patients with sickle cell disease
and pulmonary hypertension

Study Design:

To conduct a 16 week prospective open-labelled Phase II clinical trial of macitentan in SCD
patients with hemodynamics consistent with pulmonary arterial hypertension.

We plan to enroll 10 patients in this study. All enrolled patients will be treated with 10 mg
macitentan daily for the entire treatment period.

The study is comprised of the three consecutive periods:

Screening Period/Baseline Studies:

This period will be up to 30 days in duration, commencing with the first screening visit and
completing with the start of study medication.

Treatment Period:

This will begin at Visit 2, the baseline visit and will continue until the end of 16 weeks of
therapy or earlier in the case of premature stoppage of treatment. During this period, there
will be a safety assessment at the first visit followed by visits to assess safety and
efficacy at weeks 4, 8, 12 and 16.

Post-Treatment Study Period:

This will last 30 days after the completion of the treatment period and will allow for
additional assessment of medication safety.

Screening Period:

After obtaining informed consent, the patient will undergo the screening protocol which
includes assessment of baseline demographics (sex, age, race, ethnicity, height, and body
weight), as well as an assessment of why the female patients are not of child-bearing
potential as appropriate. The following data will be obtained:

1. Medical history- To include:

1. SCD related complications (stroke, AVN, priapism, lower extremity ulcers etc.)

2. Frequency of vasoocclusive crises and hospitalizations

3. Frequency of blood transfusions

4. History and frequency of acute chest syndrome

5. History of thromboembolic disease

6. History of congestive heart failure

7. History of asthma

8. History of systemic hypertension

9. History of proteinuria

10. History of chronic kidney disease

11. Echocardiogram and any data from previous echos over past 12 months

12. Pulmonary function data from the prior 12 months

2. Concomitant Medication Use - All medications will be recorded. Hydroxyurea use will be
assessed in all subjects.

3. Physical Examination and Vital Signs

4. 12 lead electrocardiogram

5. Laboratory Testing: Complete blood counts, blood chemistries including BUN and
creatinine, liver function testing, markers of hemolysis (lactate dehydrogenase, total
and indirect bilirubin, AST, reticulocyte counts), urinalysis, urine pregnancy test and
NT-pro-BNP levels.

6. WHO Functional Class

7. 6 minute walk test and Borg Dyspnea Score

8. SF-36 questionnaire

9. Right Heart Catheterization (can be done up to 12 weeks prior to initiation of study
medication).

Baseline Visit (Day 1):

1. Medical History

2. Concomitant Medication Usage

3. Physical Examination and Vital Signs

4. Laboratory and Pregnancy Testing

5. WHO functional class

6. 6 minute walk test and Borg Dyspnea Score

7. SF-36 questionnaire

Week 4 visit:

1. Physical Examination and Vital Signs

2. Laboratory and Pregnancy Testing

3. Assessment of Adverse Events

Week 8 Visit:

1. Medical History

2. Concomitant Medication Usage

3. Physical Examination and Vital Signs

4. Laboratory and Pregnancy Testing

5. WHO functional class

6. 6 minute walk test and Borg Dyspnea Score

7. SF-36 questionnaire

8. Assessment of Adverse Events

Week 12:

1. Physical Examination and Vital Signs

2. Laboratory and Pregnancy Testing

3. Assessment of Adverse Events

Week 16:

1. Medical History

2. Concomitant Medication Usage

3. Physical Examination and Vital Signs

4. Laboratory and Pregnancy Testing

5. WHO functional class

6. 6 minute walk test and Borg Dyspnea Score

7. SF-36 questionnaire

8. Assessment of Adverse Events

9. 12 lead electrocardiogram

10. Right heart catheterization

11. Echocardiogram

Post-Treatment Follow-Up Visit:

1) Assessment of Adverse Events

Inclusion Criteria:

1. A diagnosis of sickle cell disease (HbSS, HbSC, HbS- β+ or 0) confirmed by hemoglobin
electrophoresis

2. Provision of informed consent

3. Suspicion of Pulmonary Hypertension by echocardiography within the last 6 months (RVSP
> 40mmHg or a TRV > 3.0 m/sec) or diagnosis of Pulmonary Hypertension by cardiac
catheterization within the last 12 months (mean PAP ≥25 mmHg at rest). Left
ventricular ejection fraction > 50%.

4. Right heart catheterization which demonstrates the following:

1. mPAP > 25 mmHg

2. PAOP or LVEDP < 15 mmHg

3. PVR > 160 dynes-sec/cm5 or 2 Wood Units

5. Age > 18 years

6. NYHA Class II or III by symptoms

7. Six minute walk distance (6MWD) > 150 meters and < 450 meters

8. A woman of child-bearing potential is eligible only if the following applies:

1. Negative pre-treatment serum pregnancy test and agreement to monthly tests

2. Use of two highly effective methods of contraception if not truly abstinent with
a male partner OR permanent female sterilization has been performed.

9. May be on background therapy or may be treatment naïve.

Exclusion Criteria:

1. Current pregnancy or lactation

2. Any one of the following medical conditions:

1. Stroke within the last 6 weeks

2. New diagnosis of pulmonary embolism within the last 3 months

3. Clinically significant laboratory abnormalities, including, but not limited to:
Positive Hepatitis B surface antigen or Hepatitis C antibody, Positive HIV test,
Serum alanine aminotransferase (ALT) greater than or equal to 2.0 x ULN, Serum
creatinine greater than or equal to 2.5mg/dL (or calculated creatinine clearance
less than or equal to 30mL/min).

4. Hospitalization within the prior 4 weeks for a vasoocclusive crisis or acute
chest syndrome

5. Any unstable (acute or chronic) condition that in the opinion of the investigator
will prevent completion of the study

3. Evidence of diastolic dysfunction of the left ventricle as defined by a mPAP > 25 mmHg
and PCWP or LVEDP > 15 mmHg by right heart catheterization with a normal left
ventricular ejection fraction by echocardiogram or MUGA.

4. Left ventricular ejection fraction < 50% of significant ischemic, valvular or
constrictive heart disease

5. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with
study requirements (particularly the 6MWT) e.g. symptomatic hip osteonecrosis

6. Active therapy with an IV prostacyclin

7. Subjects who are taking other investigational medications at the time of the study

8. Clinically significant psychiatric, addictive (defined by DSM-IV criteria), neurologic
disease or condition that, in the opinion of the Investigator, would compromise
his/her ability to give informed consent, participate fully in this study, or prevent
adherence to the requirements of the study protocol.